Meidenbauer, Norbert and Zippelius, Alfred and Pittet, Mikael J. and Laumer, Monika and Vogl, Sandra and Heymann, Jana and Rehli, Michael and Seliger, Barbara and Schwarz, Stephan and Le Gal, Frederique-Anne and Dietrich, Pierre Y. and Andreesen, Reinhard and Romero, Pedro and Mackensen, Andreas (2004) High frequency of functionally active Melan-A-specific T cells in a patient with progressive immunoproteasome-deficient melanoma. CANCER RESEARCH, 64 (17). pp. 6319-6326. ISSN 0008-5472,
Full text not available from this repository. (Request a copy)Abstract
Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8(+) T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A(26)-(3), peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | METASTATIC MELANOMA; TUMOR-ANTIGENS; MONOCLONAL-ANTIBODIES; DENDRITIC CELLS; IN-VIVO; LYMPHOCYTES; EXPRESSION; MEMORY; GENERATION; PEPTIDE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 28 Jun 2021 12:58 |
| Last Modified: | 28 Jun 2021 12:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/37225 |
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